This research proposal is based on the hypothesis that mechanisms of autoimmunity are utilized to control or kill metastatic renal cell carcinoma (RCC), and that RCC patients who have genotypic or biologic features associated with autoimmune disorders are more likely to have favorable outcomes after treatment with immune-stimulating drugs. This project evolves from our published data demonstrating that Stage IV RCC patients carrying components of two autoimmunity-associated HLA class II haplotypes have a significantly improved response to cytokine therapy and enjoy prolonged survival. The hypothesis will be examined using a banked collection of HLA Class I and II-typed lymphoblastoid cells lines (LCL) developed from a cohort of 80 Stage IV RCC patients whose outcomes span the spectrum of prolonged disease-free survival to rapid tumor progression and death. These LCL will be used as a source of DNA for the molecular and genetic studies described herein. The research proposed in this application examines the association of RCC outcomes with three purported mechanisms of autoimmunity put forth in the clinical literature. The first mechanism, examined in Specific Aim 1, suggests that polymorphisms of the tumor necrosis factor a promoter that lead to high TNFalpha expression drive autoimmune inflammatory processes. We hypothesize that RCC patients carrying these high-expression polymorphisms have favorable outcomes after immune stimulatory therapy. This will be addressed by PCR and sequencing of the involved promoter region. The second mechanism, examined in Specific Aim 2, involves deficiencies of the complement components C4A and C4B, which are frequently observed in patients with autoimmune disease. We propose that RCC patients with genetic deficiencies in C4A or C4B have favorable outcomes. This hypothesis will be examined by molecular analysis and quantitation of C4 alleles. The third mechanism, addressed in Specific Aim 3, is based on the concept of microchimerism, the persistence of allogeneic cells in the circulation or tissues of an individual. Microchimeric cells of lymphoid origin have been proposed to be mediators of autoimmune tissue destruction. We hypothesize that RCC patients who carry microchimeric cells have favorable outcomes. Experiments are designed to detect microchimeric DNA by HLA Cw genotyping, and tumor infiltrating microchimeric leukocytes by FISH/IHC. These data will be clinically useful in predicting outcomes of RCC patients, as well as in the understanding of basic mechanisms of host-derived tumor control.